Cefotaxime and ceftriaxone have proven to be effective in pyogenic infections of the central nervous system. Since in some bacterial central nervous system infections the blood-cerebrospinal fluid (CSF) barrier is either minimally impaired or recovers in the course of the illness, we studied the penetration of both antibiotics in the absence of inflamed meninges. Patients who had undergone external ventriculostomies for noninflammatory occlusive hydrocephalus received either cefotaxime (2 g/30 min) or ceftriaxone (2 g/30 min) to treat extracerebral infections. Serum and CSF were drawn repeatedly after the first dose. With ceftriaxone, they were also drawn after the last dose. The concentrations of cefotaxime, its metabolite desacetylcefotaxime, and ceftriaxone were determined by high-performance liquid chromatography with UV detection. Maximum concentrations of cefotaxime in CSF were reached 0.5 to 8 h (median = 3 h; n = 6) after the end of the infusion and ranged from 0.14 to 1.81 mg/liter (median = 0.44 mg/liter; n = 6). Maximum levels of ceftriaxone in CSF ranging from 0.18 to 1.04 mg/liter (median = 0.43 mg/liter; n = 5) were seen 1 to 16 h (median = 12 h; n = 5) after the infusion. The elimination half-life of cefotaxime in CSF was 5.0 to 26.9 h (median = 9.3 h; n = 5), and that of ceftriaxone was 15.7 to 18.4 h (median = 16.8 h; n = 3). It is concluded that after a single dose of 2 g, maximal concentrations of cefotaxime and ceftriaxone in CSF do not differ substantially. The long elimination half-lives guarantee uniform concentrations in CSF. These concentrations reliably inhibit highly susceptible bacteria but cannot be relied on to inhibit staphylococci and penicillin G-resistant Streptococcus pneumoniae.Because of its morbidity and lethality, bacterial meningitis remains a major medical concern throughout the world. The emergence of bacteria not susceptible to standard antibacterial agents in meningitis of children and immunocompromised adults has stimulated the search for alternative drugs. Broad-spectrum cephalosporins have a broad range of in vitro antibacterial activities, including that against most organisms responsible for purulent meningitis (6,7,19), and have been successfully applied as single agents for this indication in children and adults (3,9,29,34,37 Two grams of cefotaxime (Claforan; Hoechst AG, Frankfurt/M, Germany) or 2 g of ceftriaxone (Rocephin; Hoffmann-La Roche, Grenzach-Wyhlen, Germany) was infused intravenously within 30 min. Single-dose pharmacokinetics were determined after the first infusion for six patients receiving cefotaxime and six patients receiving ceftriaxone. To obtain a 24-h time course with cefotaxime, the second infusion was administered 24 h after the first dose. Thereafter, therapy was continued with 2 g three times a day or twice a day. For this reason, patients with pneumonia or fever greater than 38.5°C during the 24-h interval before the

Inhibition of cytochrome P450OL2 activity is an important adverse effect of quinolone antibacterial agents. It results in a prolonged half-life for some drugs that are coadministered with quinolones, such as theophylline. The objective of the study described here was to define the parameters for quantifying the inhibitory potencies of quinolones against cytochrome P4501A2 in vivo and in vitro and to investigate the relationship between the results of both approaches. Cytochrome P450IA2 activity in vitro was measured by using the 3-demethylation rate of caffeine (500 FM) in human liver microsomes. The inhibitory potency of a quinolone in vitro was determined by calculating the decrease in the activity of cytochrome P450IA2 caused by addition of the quinolone (500 ,uM) into the incubation medium. The mean values (percent reduction of activity without quinolone) were as follows: enoxacin, 74.9%Yo; ciprofloxacin, 70.4%; nalidixic acid, 66.6%; pipemidic acid, 59.3%; norfloxacin, 55.7%; lomefloxacin, 23.4%; pefloxacin, 22.01%; amifloxacin, 21.4%; difloxacin, 21.3%; ofloxacin, 11.8%; temafloxacin, 10.01%; fleroxacin, no effect. The inhibitory potency of a quinolone in vivo was defined by a dose-and bioavailablity-normalized parameter calculated from changes of the elimination half-life of theophylline and/or caffeine reported in previously published studies. Taking the pharmacokinetics of the quinolones into account, it was possible to differentiate between substances with and without clinically relevant inhibitory effects by using results of in vitro investigations. The in vitro test described here may help to qualitatively predict the relevant drug interactions between quinolones and methylxanthines that occur during therapy.The fluoroquinolones have proven to be very effective antibacterial agents (2,20,23). Several new agents have been developed over the past decade. Their efficacies in controlling bacterial infections have resulted in the widespread use of these drugs.Another important biological effect of this drug class concerns the metabolism of several unrelated pharmaceutical agents, resulting in occasional adverse reactions. It has been reported that some of the quinolone antibacterial agents cause a reduced velocity of caffeine and theophylline degradation in vivo (see below) (for a review, see reference 10) and in vitro (14,40). Furthermore, reductions in the antipyrine metabolism rate and the R-warfarin oxidation rate were observed in humans when quinolones were coadministered with these drugs (23,24,46).In investigations with human liver microsomes, the mechanism of this interaction was determined for ofloxacin, ciprofloxacin, enoxacin, lomefloxacin, and pipemidic acid. A

SUMMARYCyclo-oxygenase-2-selective inhibitors produce less gastric damage than conventional non-steroidal antiinflammatory drugs. Valdecoxib is a new orally administered cyclo-oxygenase-2-selective inhibitor, recently approved for use in osteoarthritis, rheumatoid arthritis and primary dysmenorrhoea in the USA. The drug has been evaluated in more than 60 clinical studies involving more than 14 000 patients and healthy volunteers. The analgesic efficacy of valdecoxib at a dose of 10 mg once daily in both osteoarthritis and rheumatoid arthritis is superior to that of placebo and similar to that of traditional non-steroidal anti-inflammatory drugs. Valdecoxib is effective in single doses of up to 40 mg for the alleviation of acute menstrual pain and has a rapid onset of action (within 30 min) and a long duration of analgesia (up to 24 h). Valdecoxib is well tolerated and has safety advantages compared with traditional non-steroidal anti-inflammatory drugs in terms of less gastrointestinal toxicity and a lack of an effect on platelet function. The incidence of adverse effects involving the kidney (fluid retention, oedema and hypertension) is similar to that of non-selective, nonsteroidal anti-inflammatory drugs.

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A number of quinolone antibacterial agents, particularly enoxacin, pefloxacin, pipemidic acid and ciprofloxacin, are known to decrease the clearance of methylxanthines. The effects of temafloxacin and ciprofloxacin on the pharmacokinetics of caffeine were therefore compared in a 3-way crossover study in 12 healthy young volunteers. Each volunteer received 183mg once-daily doses of caffeine in conjunction with twice-daily placebo, temafloxacin 600mg and ciprofloxacin 750mg in 3 separate phases according to a randomised sequence.A doubling of the area under the plasma concentration-time curve (77.8 vs 31.8 mgfL· h) and terminal-phase half-life (9.7 vs 4.5h) of caffeine were observed in the presence of ciprofloxacin. The magnitude of the reduction in the intrinsic clearance of caffeine produced by ciprofloxacin was greater than that described in the literature for ciprofloxacin and theophylline. This may partly be explained by intertrial differences in dosage and study design.Coadministration oftemafloxacin did not have any effect on the pharmacokinetics of caffeine, confirming results of other studies suggesting that this agent does not affect methylxanthine clearance. Accordingly, it appears that restriction of caffeine intake during temafloxacin therapy is not necessary.

A rapid and sensitive method is presented for the simultaneous determination of flunitrazepam, norflunitrazepam, 7-aminoflunitrazepam, and 7-acetamidoflunitrazepam in serum, plasma, and urine. The compounds were extracted by a mixed-mode solid-phase procedure following analysis by high-performance liquid chromatography and ultraviolet detection and using methylclonazepam as the internal standard. The method revealed high recoveries and showed good precision and linearity for all compounds. The limit of detection was at least 1 ng/ml serum (plasma) for all compounds.

Certain quinolone and naphthyridone antibacterial agents reduce the clearance of theophylline, posing potential clinical risks for patients maintained on this bronchodilator. Whether temafloxacin also affects theophylline pharmacokinetics was assessed in a randomised double-blind 3-way crossover study in 12 healthy volunteers, using placebo and enoxacin as controls. Each volunteer participated in all 3 phases of the study, receiving theophylline plus daily divided doses of temafloxacin 800mg, enoxacin 800mg, or placebo, orally for 7 days. Aminophylline 200mg (containing 146mg theophylline) was given orally twice daily on the first 4 days. On the fifth morning, theophylline 200mg was administered intravenously, and serial blood and urine samples were collected for the following 72h. Coadministration of enoxacin significantly reduced the metabolic clearance of theophylline ("" 65%). In contrast, during coadministration of temafloxacin, theophylline pharmacokinetics did not differ significantly from those during coadministration of placebo. No clinically significant adverse events occurred; total reported adverse events during enoxacin-theophylline administration (n = 33) were higher than those reported during temafloxacin-theophylline administration (n = 22) and theophylline alone (n = 23). Administration of temafloxacin to patients on long term theophylline therapy appears to be a safe and rational choice when treatment with a broad spectrum antibiotic is indicated.

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